tbuckley/cabot-search huggingface dataset:
Therapeutic outcomes of lenvatinib versus sorafenib in the primary treatment of advanced hepatocellular carcinoma: A systematic review and meta-analysis.
Authors: Sidra Naz, Maha Hameed, Vikash Jaiswal, Abdelrahman M Attia, Mostafa a Soliman, Vikash Kumar, Supti Dev Nath, Dattatreya Mukherjee, Akash Jaiswal, Michelle Koifman
Journal: Journal of Clinical Oncology (2023)

e16183 Background: Molecular-targeted agents such as Lenvatinib and Sorafenib have improved survival outcomes in patients with hepatocellular carcinoma (HCC). However, using these agents in the primary treatment for advanced HCC is still under debate, with limited literature comparing the therapeutic effects of Lenvatinib versus Sorafenib. Methods: We performed a systematic literature search using the PubMed, Embase, Scopus, and Cochrane libraries for relevant articles from inception until 10th February 2023. Results: A total of 8 studies with 1995 patients (955 Lenvatinib vs. 1040 Sorafenib) were included in our analysis. The mean age of the patients in both groups was comparable (65 vs. 66) years. The overall survival was also comparable between the groups (HR = 0.83; 95%CI: 0.67-1.02; p = 0.08). However, progression-free survival (HR = 0.83; 95%CI: 0.77-0.89; p&lt;0.00001) and time to progression (HR = 0.69; 95%CI: 0.51-0.93; p = 0.02) were significantly improved in the Lenvatinib group compared to Sorafenib. The pooled analysis showed that the treatment response evaluated through the Objective response rate (OR = 7.37; 95%CI: 1.86-29.20; p = 0.004) and Disease control rate (OR = 3.03; 95%CI: 0.98-9.30; p = 0.05) of the Lenvatinib group were better than those of the Sorafenib group. However, the likelihood of severe adverse events (OR = 1.76; 95%CI: 1.38-2.24; p &lt;0.00001) was significantly higher in the Lenvatinib group compared with Sorafenib patients. In addition, among common adverse events, hypertension (HR = 2.68; 95%CI: 1.48-4.83; p = 0.001) and fatigue (HR = 2.53; 95%CI: 0.90-7.13) were significantly higher among Lenvatinib group compared to Sorafenib. Conclusions: In the primary treatment of advanced HCC, Lenvatinib significantly improves progression-free survival, time to progressions, and objective response rate. However, the likelihood of severe and common adverse events such as hypertension and fatigue are significantly higher after using Lenvatinib than Sorafenib. [Table: see text]
Effect of trametinib and anti-PD-1 combo on tumor growth and survival of <i>KRAS</i>-mutant lung cancer by ID1 downregulation.
Authors: Ander Puyalto Calvo, María Rodríguez-Remírez, Ines Lopez, Maria Olmedo, Anna Vilalta, Irati Macaya, Connor Welch, Silvestre Vicent, Alfonso Calvo, Daniel Ajona, Ignacio Gil-Bazo
Journal: Journal of Clinical Oncology (2023)

e14633 Background: Although anti-PD-1/PD-L1 antibodies represent a major breakthrough in NSCLC patients’ survival, this treatment efficacy is highly dependent on tumor PD-L1 expression. We reported the role of ID1 and the efficacy of a combined blockade of PD-1-ID1 in a KRAS mutant NSCLC mouse model (Baraibar et al; Cancers 2020). Trametinib, which is an oral MEK1/2 inhibitor, acts downstream of KRAS. Here we evaluate trametinib as an ID1 inhibitor able to enhance immunotherapy efficacy through PD-L1 overexpression. Methods: To explore whether MEK1/2 inhibition reduces ID1 expression in vitro and in vivo, experiments in NSCLC cells (human and murine) and in murine models were performed. RNAseq analysis was conducted to elucidate the pathways implicated in ID1 inhibition. Trametinib resistant (TR) cells were generated to analyze the effect of ID1 in the acquired resistance to treatment. Apoptosis was measured by flow cytometry. PD-L1 expression was evaluated by flow cytometry in control, ID1 silenced, ID1-overexpressing and TR cell lines. Treatment of trametinib combined with anti-PD1 was performed in KRAS-mutant LUAD models. Results: In vitro experiments in NSCLC cells showed ID1 inhibition at protein level after MEK1/2 blockade. However, we observe an increase in ID1 mRNA levels following treatment. In vivo experiments performed in C57BL6J and in ID1-deficient mice showed no significant differences in tumor growth between ID1 knock-out and ID1 wild-type mice treated with trametinib. IHC analysis of those tumor samples showed reduced ID1 levels (LLC p&lt;0.001; CMT-167 p&lt;0.0001). RNAseq analysis revealed an enrichment of ubiquitin-proteasome pathway after trametinib exposure. Blockade of proteasome activity with a specific inhibitor, restored ID1 levels. TR cells did not show MEKi induced ID1 inhibition, moreover, ID1 blockade rescued the sensitivity to trametinib in human and murine NSCLC TR cells (p&lt;0.001). Flow cytometry analysis showed increased PD-L1 expression (p&lt;0.001) in human and murine NSCLC cell lines after trametinib administration. In contrast, ID1-overexpressing cells and TR cells did not show PD-L1 upregulation after MEK inhibition. In vivo experiments confirmed the therapeutic efficacy of trametinib and anti-PD-1 combo, reducing tumor growth (p&lt;0.05) and increasing mice survival (p&lt;0.05), compared with trametinib monotherapy or immunotherapy alone. Conclusions: Pharmacological inhibition of MEK1/2 decreased ID1 expression in vitro and in vivo, replicating the effect of a specific shRNA against ID1, through proteasome activation. PD-L1 upregulation induced by ID1 blockade after trametinib treatment sensitized KRAS-mutant NSCLC cells to PD-1/PD-L1 immunotherapy, blocking tumor growth and improving overall survival.
Is laparoscopic approach feasible in early-stage ovarian cancer? A retrospective study in single tertiary center.
Authors: Chen Bin Chang
Journal: Journal of Clinical Oncology (2023)

e17560 Background: Laparoscopic approach for early-stage ovarian cancer is a controversy. Current studies showed no negative impacts on these patients. However, some limitations were noted, such as small case numbers, heterogeneity, and retrospective study. Methods: We retrospectively reviewed our cases who was diagnosed as early-stage ovarian cancer and received staging surgery from 2009 through 2017. There patients were divided into two groups, via laparoscopic staging or laparotomy. The primary outcome was progression-free survival. The secondary outcomes were overall survival and intra-operative rupture rate. We performed the Kaplan-Meier method and chi-square test for analyzing survival outcome and factors, in order to evaluate impacts on different surgical methods. Results: Total 520 patients (2014 FIGO stage IA-IC3) were enrolled, including 355 patients who underwent open surgery and 165 patients who underwent laparoscopic surgery. The median follow-up time for survivors was 71(range,39.7-102.3）months. The progression-free survival was similar between two groups and all subgroups. The overall survival was also similar between two surgical methods and all subgroups, except subgroup of clear cell carcinoma. The p-value of overall survival in clear cell carcinoma patients was 0.05. However, the case numbers of clear cell carcinoma 81 in laparotomy group and 31 in laparoscopy group, respectively. The intra-operative rupture rate was increased in laparoscopic group. The relative risk and p-value were 1.139 and 0.043, respectively. Conclusions: Laparoscopic may be feasible in early-stage ovarian cancer in selected patients and expert surgeon due to higher intra-operative rupture rate. If clear cell carcinoma of ovary was highly suspected, the surgeon should be alerted because poorer overall survival in clear cell carcinoma of ovary patients was observed.
Effect of FAPα-expressing tumor cell vaccine with PD-1 mAb on its efficacy in mice colorectal cancer model.
Authors: Hongyuan Jia, Meihua Chen, Ling Xiao, Tao Li, Jingyi Lang
Journal: Journal of Clinical Oncology (2023)

e14615 Background: Colorectal cancer (CRC) is the third prevalent malignant tumor all over the world, and many cases are metastatic at diagnosis. Immunotherapy emerges a promising treatment in CRC. However, anti-PD-1 monotherapy alone has not yielded a clinical benefit in majority of these patients. Therefore, combination therapy is necessary to overcome this limitation. Previously, we have developed a FAPα-expressing tumor vaccine and demonstrated its anti-tumor effects by reversing of immunosuppressive tumor microenvironment (TME). In the current study, we hypothesized that combination therapy could enhance the effect of anti-PD1 therapy. Methods: FAPα-expressing CT26 cells were produced as previously described. To establish xenograft tumor model, CT26 cells were injected into left flank of BALB/c mice. Anti-PD-1 monoclonal antibodies(mAb) were injected intraperitoneally twice weekly up to 5 injections. FAPα-vaccines were injected subcutaneously around tumors weekly up to 3 injections. Histological sections of tumours were analysed by H&amp;E staining and immunofluorescence. Flow cytometric analysis was done using an FACSCalibur (BD) and analyzed using FlowJo software (TreeStar). Gene expression profile in TME was analyzed by bulk RNA sequencing. Results: In mice xenograft CT26 tumor model, either anti-PD-1 immunotherapy or FAPα tumor cell vaccine produced suppression of CT26 tumor growth compared with the control group. However, combining anti-PD-1 mAb and FAPα-expressing tumor cell vaccine elicited the most remarkable anti-tumor effect and induced the most pronounced tumor growth suppression among all groups. In combination therapy group of the vaccine and PD-1 mAb, there were significantly more infiltrated lymphocytes and less FAPα+ fibroblasts. Flow cytometry demonstrated that the combination therapy promoted M1 macrophage polarization with a reduction of M2-like tumor associated macrophages (TAMs) and an increase of M1-like TAMs. This polarization was in consistent with the reduced level of IL-10 that is predominant cytokine secreted by M2 macrophages. A reduction of myeloid-derived suppressor cells (MDSCs) in the TME were also observed. Using bulk RNAseq we observed a set of immune related genes upregulated following combination therapy, including innate immune response, antigen presentation, lymphatic cells and recruitment and T cells activation. Decreased secretion of immune inhibitory chemokines (eg, CXCL12, IL-10, TGFβ) was also found by ELISA in tumors from mice treated with combination therapy. Conclusions: Our preliminary results suggested that combination therapy of FAPα-expressing tumor vaccine and anti-PD-1 therapy is a promising way to improve the efficacy of immunotherapy through modulation of immunosuppressive TME. In the future, more research is needed to further elucidate mechanism and clinical value of this combination approach.
Pediatric carcinoid tumors of the lungs: A descriptive analysis.
Authors: Dong-jin Joshua Lee, Joseph Largen, Kaamil Abid, Robert W. Hu
Journal: Journal of Clinical Oncology (2023)

e22017 Background: From 1973 to 2012, the prevalence of neuroendocrine tumors in children was found to have increased by approximately 6-fold when using the Surveillance Epidemiology, and End Results. While carcinoid tumors in adults are mostly indolent, pediatric carcinoid tumors tend to carry worse prognoses. Our goal for this study is to describe the population of pediatric patients with pulmonary carcinoid tumors. Methods: We used the National Cancer Database to identify pediatric patients diagnosed with carcinoid tumors of the lungs between 2004-2020. Analysis was conducted with SPSS to determine frequency of cases in different demographics. Survival was assessed using Kaplan-Meier curves with significance set at p &lt; 0.05. Results: Of the 125 patients identified, 55% of the patients were male and 45% female. Pulmonary carcinoid tumor patients were predominately white accounting for 80% of all cases. Black patients accounted for 14% of cases. The ages of diagnosis ranged from 3-17 years of age with the mean being 14.5 years of age. The majority of patients were diagnosed during their teenage years–84% were between the ages of 13 and 17 at diagnosis. Only one case was observed in a patient of age 6 or under. The median survival was 89 months. Univariate analysis revealed no significant difference in survival was seen in sex, race, or insurance groups. Charlson-Deyo score, however, did impact survival, where patients with a score of 2 had lower median survival time (36 months) compared to patients with a score of 1 (121 months) or 0 (87 months). Conclusions: Pediatric pulmonary carcinoid tumors are more commonly seen in white patients with most diagnoses occurring during patients’ teenage years (13-17). Age, sex, and race did not have a significant effect on survival although a Charlson-Deyo score of 2 was indicative of a worse prognosis when compared to a score of 1 or 0.
Comparison of first-line treatments for recurrent or metastatic nasopharyngeal carcinoma based on phase 3 randomized clinical trials.
Authors: Wei Xiong, Lixiu Zhu, Guoqiang Xu, Yaoxiong Xia, Hu Wang, Tianrui Xu, Xin Li, Yongyuan Xue, Zhengfei Li
Journal: Journal of Clinical Oncology (2023)

e18012 Background: Guidelines recommend platinum-based chemotherapy as first-line treatment for recurrent or metastatic nasopharyngeal carcinoma (R/M NPC) patients. There are a variety of available combination treatment options, however, there is lack of research evaluating their advantages and disadvantages. Therefore, this study aims to compare the efficacy and adverse events (AEs) of the first-line treatment for R/M NPC. Methods: PubMed, EMBASE, Web of Science, and the Cochrane Library were systematically searched for phase 3 randomized clinical trials (RCTs) in which two first-line treatments for R/M NPC were compared. Among the included trials, progression-free survival (PFS) and overall survival (OS) were calculated using the hazard ratio (HR) and 95% Bayesian confidence interval (95% CrI), while the odds ratio (OR) and 95% CrI were used to evaluate the incidence of severe AEs. The cumulative ranking plot and surface under the cumulative ranking curve (SUCRA) were used to evaluate the rank probability of each regimen. Results: Three trials involving 4 total regimens were included. In terms of PFS, toripalimab plus gemcitabine plus cisplatin (GP) (HR: 0.28; 95% CrI: 0.081-0.98) and camrelizumab plus GP (HR: 0.28; 95% CrI: 0.079-0.96) were significantly superior to fluorouracil plus platinum (PF). In the rank analysis, camrelizumab plus GP was most likely to be the best regimen (SUCRA = 0.81), followed by toripalimab plus GP (SUCRA = 0.80). There was no significant difference among these treatments in terms of OS or AEs. Conclusions: This is the first network meta-analysis comparing the pros and cons of first-line regimens for R/M NPC based on phase 3 randomized clinical trials. Our research showed that toripalimab/camrelizumab plus GP was found to be the most effective treatment regimens for the first-line treatment for R/M NPC in terms of PFS.
The exploratory case-control study on prediction of immune checkpoint inhibitor-induced thyroiditis by human leukocyte antigen types.
Authors: Yutaka Natori, Eisaku Sasaki, Junko Suga, Reiko Kimura-Tsuchiya, Emi Tokuda, Shigehira Saji
Journal: Journal of Clinical Oncology (2023)

2558 Background: Given the function of human leukocyte antigen (HLA) in immunity, variation of the HLA type could affect the development of immune-related adverse events (irAEs) that is induced by immune checkpoint inhibitors (ICIs). In this study, we examined whether HLA types of cancer patients could be a marker for the development of irAE thyroiditis. Methods: In the present case-control study, we randomly selected 20 cancer patients who received ICIs and developed thyroiditis (irAE thyroiditis group) and 51 who did not develop thyroiditis (No irAE thyroiditis group). The 51 patients were subdivided into 31 who did not develop any irAEs (No irAEs group) and 20 who developed irAEs other than thyroiditis (irAEs other than thyroiditis group). HLA types were classified at the amino acid sequence level (Field 2 resolution). Frequency of the HLA types of each group was compared. Results: There was no significant difference in HLA type prevalence, comparing the irAE thyroiditis group and the No irAE thyroiditis group. When comparing the irAE thyroiditis group with the No irAEs group, the irAE thyroiditis group had significantly higher HLA-X, HLA-Y, and HLA-Z (Tentative names are used here, and actual HLA types will be announced at the time of publication). This result suggested that irAEs other than thyroiditis in the control group could be noise. HLA-X had a specificity of 96.8% for the development of irAE thyroiditis. HLA-Y had a sensitivity of 80.0%. Patients carrying both HLA-X and HLA-Y had the highest specificity of 100.0%. There was a significant difference in frequency of HLA-Y between irAEs other than the thyroiditis group and the No irAEs group. HLA-Y may be a universal marker for any irAEs. On the other hand, HLA-X is a specific marker for thyroid irAE. The median time of onset of irAE thyroiditis in all patients was 72 days after ICI administration. Patients with both HLA-X and HLA-Y tended to have an earlier onset with a median onset time of 53 days. Conclusions: We found an association between specific HLA types and the development of irAE thyroiditis. The present study indicates that HLA types could be a predictive marker for the development of irAE thyroiditis.
Evaluation of change in RECIST tumor size and survival in patients with rare cancers treated with checkpoint inhibitor therapy (SWOG S1609).
Authors: Megan Othus, Sandip Pravin Patel, Young Kwang Chae, Eliana Dietrich, Howard Streicher, Elad Sharon, Razelle Kurzrock
Journal: Journal of Clinical Oncology (2023)

2504 Background: RECIST has been used for over twenty years to evaluate changes in tumor burden. At each scan, the sum of maximum diameters of “target” lesions are measured. Changes in the sum are categorized into an “objective status” at each scan, including complete and partial response and stable and progressive disease. Prior research among patients treated with chemotherapy did not find a threshold effect corresponding to the RECIST categories; instead a linear association was observed. Herein we use a unique clinical trial resource, a basket trial of patients with rare cancer treated with combination anti-CTLA-4 and anti-PD-1 therapy, to evaluate the association between quantitative change in RECIST tumor burden and survival among patients treated with checkpoint inhibitor therapy. Methods: The study population was 796 patients enrolled on the S1609 DART (Dual Anti-CTLA-4 &amp; Anti-PD-1 blockade in Rare Tumors) trial, a basket immunotherapy trial evaluating ipilimumab plus nivolumab across solid rare tumor subtypes. The analysis population was 720 patients; patients not eligible (n=50; mostly due to non-rare diagnosis), THOSE who did not receive protocol therapy (n=22), OR WHOSE DISEASE WAS NOT evaluated by RECIST (n=4; gestational trophoblastic disease evaluated by -hCG) were excluded. All patients had RECIST-measurable disease at study entry. Associations between overall and progression-free survival (OS and PFS) and change in tumor burden between baseline and the first scan were evaluated using log-rank tests and Cox regression models stratified by basket. Landmark analyses (at day 65) controlled for lead-time bias. Linear regression models and R 2 were estimated for median and 2-year estimates across tumor change intervals. Results: The median age of the cohort was 61, 52% werethe distribution of percent change in tumor burden at the first scan. The linear correlation between median and 6-month PFS and change in tumor burden had R 2 = 0.92 and 0.74.; median and 1-year OS had R 2 = 0.79 and 0.79. Martingale residuals for both PFS and OS showed linear trends up to tumor increase of +50% with no thresholds at definitions of partial response or stable disease. Conclusions: This is the first evaluation of the association between numeric changes in RECIST tumor burden among patients receiving checkpoint therapy. Our results suggest that similar to results among patients who received chemotherapy there is a linear correlation with PFS and OS. As a consequence, the thresholds for RECIST categories do not correspond to thresholds in patient outcomes. [Table: see text]
KEYVIBE-010: Adjuvant coformulated vibostolimab with pembrolizumab versus adjuvant pembrolizumab in patients with high-risk stage II-IV melanoma.
Authors: Georgina V. Long, Alexander M. Eggermont, Jeffrey E. Gershenwald, Dirk Schadendorf, Paolo Antonio Ascierto, Reinhard Dummer, Axel Hauschild, Matteo S. Carlino, Antoni Ribas, Caroline Robert, Richard A. Scolyer, Vernon K. Sondak, Jonathan E Cohen, Jinchun Zhang, Dmitri O. Grebennik, Clemens Krepler, Jason J. Luke
Journal: Journal of Clinical Oncology (2023)

TPS9611 Background: Pembrolizumab is an anti−PD-1 monoclonal antibody that has been shown to significantly improve recurrence-free survival and distant metastasis-free survival when used as adjuvant therapy in patients with high-risk resected melanoma (Long GV, et al. Lancet Oncol. 2022;23:1378-88; Eggermont AMM, et al. Lancet Oncol. 2021;22:643-54). Combining pembrolizumab with other therapies may further improve outcomes in this setting. Vibostolimab is an anti-TIGIT monoclonal antibody that showed antitumor activity and manageable safety when used in combination with pembrolizumab in patients with advanced solid tumors in the phase 1 KEYVIBE-001 study (Niu J, et al. Ann Oncol. 2022;33:169-80). The randomized, double-blind, phase 3 KEYVIBE-010 study (NCT05665595) is designed to evaluate the efficacy and safety of adjuvant coformulated vibostolimab and pembrolizumab (MK-7684A) versus pembrolizumab alone in patients with resected high-risk stage IIB-IV melanoma. Methods: Eligible patients are ≥12 years of age (weighing ≥40 kg if &lt; 18 years), with surgically resected stage IIB or IIC (pathologic or clinical), III, or IV cutaneous melanoma per AJCC 8th edition guidelines, and an Eastern Cooperative Oncology Group performance status of 0 or 1 (Lansky play-performance scale ≥70 if &lt; 16 years; Karnofsky performance status ≥70 if ≥16 to &lt; 18 years). Patients must not have received any prior systemic therapy beyond complete resection and no more than 12 weeks can have elapsed between final surgical resection and randomization. Patients with ocular, mucosal, or conjunctival melanoma, and prior allogeneic tissue/solid organ transplant are excluded. Patients will be stratified by risk. Approximately 1560 patients will be randomly assigned 1:1 to receive intravenous coformulated vibostolimab 200 mg with pembrolizumab 200 mg or pembrolizumab 200 mg (2 mg/kg up to a maximum of 200 mg for adolescents) every 3 weeks. Treatment will continue for 17 cycles or until disease recurrence, unacceptable toxicity, or withdrawal. The primary end point is recurrence-free survival by investigator review. Secondary end points are distant metastasis-free survival by investigator review, overall survival, safety and tolerability, and quality of life. Hazard ratios and 95% confidence intervals will be estimated using a stratified Cox regression model with the Efron method of handling ties, with treatment as a covariate. Between-treatment differences will be evaluated using a stratified log-rank test. Enrollment is ongoing. Clinical trial information: NCT05665595 .